In Korea, dietary fat intake has recently increased with the growth of economy and the westernization of diet life, and onset of metabolic diseases such as obesity, diabetes, hyperlipidemia, hypertension, arteriosclerosis, and fatty liver are increasing due to insufficient exercise. In addition, obesity not only hurts the beauty of younger people who likes slim body shape, but also is associated with various disorders as obesity continues.
At present, therapeutic agents for obesity may be broadly classified into drugs that act on the central nervous system to affect appetite, and drugs that act on the gastrointestinal tract to inhibit uptake. Drugs acting on the central nervous system are commercially available as anti-obesity drugs which inhibit the serotonergic (5-HT) nervous system such as fenfluramine and dexfenfluramine, act through the noradrenergic nervous system such as ephedrine and caffeine, and act on both the serotonergic and the noradrenergic nervous systems such as recently developed sibutramine, according to their respective mechanisms. In addition, representative anti-obesity drugs acting on the gastrointestinal tract are orlistat, etc., approved as a therapeutic agent for obesity, which inhibits intestinal lipase to reduce fat uptake.
However, there are problems with some of the existing drugs. For example, drugs such as fenfluramine have been recently prohibited from being marketed due to the side effect of incurring primary pulmonary hypertension or valvular heart disease, and other drugs cannot be also used to patients suffering from heart failure or kidney disease due to the occurrence of decreased blood pressure or lactic acidosis.
Diabetes is a type of metabolic disorder caused when insulin is insufficiently secreted or normal function is not achieved (DeFronzo, 1988), and is characterized by hyperglycemia with high blood glucose levels, which causes a variety of symptoms and signs and makes glucose excreted into urine. Recently, the incidence of diabetes has explosively increasing due to the increase in obesity rate, especially abdominal obesity.
The number of diabetic patients was estimated to be 170 million worldwide in 2000 and expected to reach 370 million in 2030. However, it has recently been reported that the number of diabetic patients already reached 350 million worldwide in 2008, which is far worse than expected (Danaei et al., 2011). It is reported that more than about 80% of type 2 diabetic patients are obese, while only less than 10% of obese patients have diabetes (Harris et al. 1987).
The relationship between diabetes and obesity is attributed to the fact that adipokines and free fatty acids are irregularly secreted to cause fatty acids to accumulate in insulin-sensitive tissues such as the beta cells, kidneys, liver, heart, etc., resulting in lipotoxicity. If chronic hyperglycemia is not treated properly, it is accompanied by various pathological symptoms such as retinopathy, renal dysfunction, neuropathy, and vascular disorder in the body. Effective management of blood sugar levels is essential to prevent such complications.
Currently, the method of controlling blood sugar levels is accomplished by lifestyle improvement (for example, diet therapy and exercise therapy), drug therapy, etc. However, diet therapy or exercise therapy is difficult to strictly manage and implement, and there are limitations in its effects. Thus, most of diabetic patients rely on the control of blood sugar levels by drugs such as insulin, insulin secretagogues, insulin sensitizers, and hypoglycemic agents, as well as lifestyle improvement.
Insulin produced by a recombinant method is an essential drug for type 1 diabetic patients and type 2 diabetic patients which fail to control blood sugar levels, and is advantageous in the control of blood sugar levels. However, it has the disadvantages such as repulsion to injection needles, difficulty in administration method, risk of hypoglycemia, and weight gain.
Meglitinides, a kind of insulin secretagogues, are very short-acting agents which are taken before meals, and include NovoNorm (repaglinide), Fastic (nateglinide), Glufast (mitiglinide), and the like. Insulin sensitizers are characterized by causing little hypoglycemia when taken alone, and include biguanide drugs such as metformin, thiazolidinedione drugs such as Avanida (rosiglitazone) and Actos (pioglitazone), and the like.
Recently, GLP-1 agonists have been developed using the action of glucagon-like peptide-1, a hormone that promotes insulin secretion, and include exenatide and Victoza (liraglutide). In addition, dipeptidyl peptidase-4 (DDP-4) inhibitors that inhibit the action of DPP-4, an enzyme that rapidly inactivates GLP-1, are recently developed drugs, and are representatively exemplified by Januvia (ingredient name: sitagliptin).
However, these drugs have been reported to have side effects such as hepatoxicity, gastrointestinal disorders, cardiovascular diseases, and carcinogenicity. The annual cost of treatment with these drugs is also high, thereby making it a barrier to the treatment of diabetes. Indeed, health care costs of pre-diabetes and diabetes are close to about KRW 200 trillion in the US in 2007 (Dall et al., 2010), and health care costs of obesity are also approaching about KRW 150 trillion in the US in 2008 (Finkelstein et al., 2009). Therefore, there is an urgent need for the development of a drug which can effectively lower blood sugar levels to be applied to the treatment of both diabetes and obese type diabetes, while having few side effects.